Substituted 2-aminobenzoxazoles are ubiquitous scaffolds featured in a wide variety of therapeutic agents or as key intermediates in the synthesis of therapeutic agents. Such agents include; dopamine antagonists, 5-HT3 partial agonists, TIE-2 inhibitors, FKBP inhibitors, IMPDH inhibitors, PPARα and PPARγ antagonists, HIV reverse transcriptase inhibitors, leukotriene biosynthesis inhibitors, bombesin receptor antagonists, intergrin receptor ligands, platelet ADP receptor ligands, CCR3 receptor antagonists, fungicides, sedatives, and muscle relaxants.
Known methods for preparing substituted 2-aminobenzoxazoles include cyclodesulfurization, which involves the cyclization of a thiourea under oxidative conditions. (cf. J. Heterocyclic Chem. 1990, 27, 221; Tetrahedron Lett. 1999, 40, 1103; Chem. Pharm. Bull. 1981, 29, 1518; Chem. Lett. 1986, 8, 1291; WO9840381-A1; Chem. Pharm. Bull. 1992, 40, 1424) The thiourea is typically generated by reacting an aminophenol with a thioisocyanate. In many of the reported examples, a toxic metal oxide, e.g. HgO, PbO, or a potentially explosive oxidant, e.g. NaOCl, K2O, is employed.
Another method for synthesizing 2-aminobenzoxazole compounds involves the nucleophilic displacement reaction of a 2-substituted benzoxazole, wherein the 2-substituent may be sulfur, thiomethyl, halogen or phenoxide, with an amine. (cf. J. Med. Chem. 1998, 41, 3015; Synthesis, 1994, 1124; Pharmazie, 1997, 52, 585) Such methods typically require the use of a scrubber system to oxidize generated methanethiol or hydrogen sulfide, or a reactive reagent such as phosphorous oxychloride to form the 2-chlorobenzoxazole intermediate.
Several procedures have been reported wherein a substituted 2-aminobenzoxazole can be produced directly from a 2-aminophenol. (Synth. Commun. 1990, 20, 2327; J. Heterocyclic Chem. 1987, 24, 275; Synthesis, 1991, 753; J. Heterocyclic Chem. 2006, 43, 599; Tetrahedron, 2004, 60, 9883) Such methods, which involve an imidate and thioimidate based reagent, iminium salts, cyanogen bromide, or 1,1-diimidazoleimine, require the formation of the imidate or salt prior to cyclization, and may further entail the use of hazardous reagents or elaborate purification procedures.
A process for preparing substituted 2-aminobenzoxazoles from 2-aminophenols and thioisocyanates with transition metals is described in US Pat. Appl. Serial No. 20030109714-A1, the disclosure of which is incorporated herein by reference. In a further elaboration of this method, substituted 2-aminobenzoxazoles are prepared from 2-aminophenols and thioisocyanates via an oxidative desulfurization utilizing hydrogen peroxide and lithium hydroxide. (cf. Tet. Lett, 2005, 46, 8341)
A method for constructing a variety of substituted 2-aminobenzoxazoles that is convenient, efficient, versatile, and amenable to large-scale production would be highly desirable. Such a method is realized in the present invention.